The present work proposes to examine the physiological and pharmacological paramters producing and modulating the release of substance P, an 11-amino acid peptide, from the spinal cord in the unanesthetized rat and cat. Employing spinal perfusion procedures, studies will be carried out to determine whether the release of substance P is associated with activity in a specific population of peripheral afferent nerves. On the basis of preliminary experiments, there is reason to believe that the substance P released from the superficial layers of the spinal cord derives from the activity in small, high threshold fibers, but not from the activity of large fibers. The experimental sequence will seek to verify whether the observed release is indeed from small fibers and determine whether the observed evoked release is modulated by physiologically (brainstem raphe magnus and dorsal columns) or pharmacologically (GABA, glycine and serotonin) identifiable systems known to exist within the dorsal horn. Of particular importance is the possibility that the analgetic effects produced by opiates (with an action limited to the spinal cord) is in part mediated by a blockade of substance P release in the spinal cord. Evidence for such a blockade has been suggested from in vitro and preliminary in vivo experiments. The present investigations will ascertain the potency of the interaction by examining the effects of opiates on the release of substance P from the cord in the intact animal and seek to determine the pharmacological specificity of the effect. Therefore, examination of the factors associated with the in vivo release of substance P and the fiber systems mediating and modulating this release represents the principal theoretical thrust of this proposal. In a practical framework, should the disposition of substance P in the spinal cord be associated with a specific category of primary afferents which mediate nociceptive input, future research might be suggested in which the pharmacological manipulation of substance P in the spinal cord might be associated with a functionally specific change in the response to pain.